Development of Polycystic Kidney Disease in Juvenile Cystic Kidney Mice

Abstract

Significant progress in understanding the molecular mechanisms of polycystic kidney disease (PKD) has been made in recent years. Translating this understanding into effective therapeutics will require testing in animal models that closely resemble human PKD by multiple parameters. Similar to autosomal dominant PKD, juvenile cystic kidney (jck) mice develop cysts in multiple nephron segments, including cortical collecting ducts, distal tubules, and loop of Henle. The jck mice display gender dimorphism in kidney disease progression with more aggressive disease in male mice. Gonadectomy experiments show that testosterone aggravates the severity of the disease in jck male mice, while female gonadal hormones have protective effects. EGF receptor is overexpressed and mislocalized in jck cystic epithelia, a hallmark of human disease. Increased cAMP levels in jck kidneys and activation of the B-Raf/extracellular signal-regulated kinase pathway are demonstrated. The effect of jck mutation on the expression of Nek8, a NIMA-related (never in mitosis A) kinase, and polycystins in jck cilia is shown for the first time. Nek8 overexpression and loss of ciliary localization in jck epithelia are accompanied by enhanced expression of polycystins along the cilia. The primary cilia in jck kidneys are significantly more lengthened than the cilia in wild-type mice, suggesting a role for Nek8 in controlling ciliary length. Collectively, these data demonstrate that the jck mice should be useful for testing potential therapies and for studying the molecular mechanisms that link ciliary structure/function and cystogenesis.

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“…1). (28) Serum BUN and creatinine levels were monitored over a period ranging from 6 to 18 weeks of age in female jck and WT controls. As expected, WT mice maintain their serum BUN within the normal range (22.50 AE 0.43 mg/dL), whereas jck mice exhibit a gradual increase in both serum BUN (Fig.…”

“…(26,53,54) We have extended these studies by characterizing the natural progression of CKD-MBD in the jck mouse, a genetic model of PKD, (28) as a first step toward defining the mechanistic link between renal dysfunction, declining bone, and cardiovascular disease. Importantly, we confirm that changes in jck serums closely mirror those observed in clinical serum samples as reported by Craver and colleagues, (29) albeit with some differences (Fig.…”

“…Characterization of these mice has been described. (28) Mice were maintained in a virus-and parasite-free barrier facility and exposed to a 12-hour light/dark cycle. WT animals were maintained on standard rodent chow diet (PicoLab Rodent Diet 20, #5053; LabDiet, St. Louis, MO, USA) containing 0.63% phosphate, 0.81% calcium, with 2.2 IU/g Vitamin D 3 .…”

“…Female mice were used because the progression of renal disease occurs slower relative to male jck mice, providing a broader window to capture early events. (28) Serum and urine analysis Whole blood was collected under isoflurane anesthesia via retroorbital bleed, incubated for 20 minutes at room temperature, and then centrifuged at 48C. Serum was aliquoted and frozen at À808C for subsequent analysis.…”

“…(28) jck mice develop concurrent serum biochemical changes characteristic of human CKD-MBD, (29) with approximately 40% to 60% of jck mice also developing vascular calcification and initial stages of LVH. Histomorphometric analysis revealed the presence of high-turnover (HTO) bone disease prior to a significant elevation of serum parathyroid hormone (PTH).…”